1. Field of the Invention
The present invention relates generally to the fields of cell biology, developmental biology and neurobiology. More particularly, it concerns methods and compositions relating to the induction of neural differentiation in stem cells.
2. Description of Related Art
Extensive evidence suggests that new neurons originate from stem cells in the adult mammalian hippocampus, a region of the brain that is important for learning and memory. The differentiation of stem cells into neurons begins within a month of the birth of a cell and continues throughout the adult life of the mammal (Gage et al. 1995). Hippocampal neurogenesis is a mechanism for maintaining cellular homeostasis in the adult brain and plays an important functional role in higher cerebral activities like learning and memory. While exercise and exposure to an enriched environment promote adult hippocampal neurogenesis, chronic stress, depression, sleep deprivation and aging can decrease neural stem/progenitor cell proliferation in the adult hippocampus.
In the mammalian central nervous system, adult multipotent neural progenitor cells cultured in the presence of retinoic acid (RA) differentiate into neurons (Palmer et al., 2001; Ray and Gage, 2006). By contrast, when such cells are cultured in the presence of insulin-like growth factor I (IGF-I) or leukemia inhibitory factor (LIF) plus bone-morphogenetic protein (BMP), they differentiate into oligodendrocytes and astrocytes, respectively (Hsieh et al. 2004). The cellular and molecular mechanisms that control the differentiation of adult hippocampal neural progenitor cells into neurons, oligodendrocytes and astrocytes are not completely understood.
Compounds that selectively direct stem cell fate could be useful for the treatment of neurodegenerative and psychiatric diseases and in the repair and regeneration of the nervous system. Chemicals can be identified that not only strongly favor neuronal differentiation, but also actively suppress astrocyte and oligodendrocyte differentiation. In addition, neurons whose differentiation has been induced in vitro could be used for stem cell grafting and transplantation. Ultimately, the study of multipotent neural progenitor cells in culture can be applied to studies of neurogenesis and gliogenesis in vivo, both in normal and in diseased and malignant states. Accordingly, potent inducers of neuronal differentiation of neural stem cells merit investigation.
As a corollary to the ability of a chemical compound to induce neurogenesis in a neural stem/progenitor cell, such a compound might also be an effective differentiation-inducing anti-neoplastic agent. Increasing evidence indicates that stem cells lie at the root of brain tumors like glioblastoma multiforme (GBM). Small-molecules that are active in neural stem/progenitor cells might therefore also have bioactivity against the brain tumor stem cell. Thus, small-molecules that induce neural stem cell differentiation might also be useful for arresting growth, killing, or differentiating GBM cancer stem cells, currently thought to be the cause of one of the most devastating and incurable of human malignancies.
Moreover, evidence is accumulating that primitive cancerous stem cells for hematopoietic cancers and several types of solid tumors exist. See, e.g., Cooper; 1992; Bonnet and Dick, 1997; Park et al., 1971; Hamburger and Salmon, 1977; and U.S. Pat. No. 4,411,990. Current methods for diagnosing or treating cancer, removing cancer cells from transplant grafts prior to injection into a patient, or methods to screen the efficacy of anti-cancer agents in completely eliminating cancer cells, do not account for the presence of cancer stem cells, which can propagate, differentiate into mature cancer cells and self-renew, thereby reforming cancers and leading to remissions. Accordingly, there exists a need for new methods for treating cancer which account for and/or are specifically directed to cancer stem cells.